TMS and other forms of non-invasive brain stimulation (NIBS) are being tested for an increasing range of conditions, most recently leading to approval for the treatment of obsessive-compulsive disorder. The mechanisms responsible for the effects of treatment, however, remain largely unknown. In the context of Alzheimers disease (AD), although a number of small clinical trials have reported potentially encouraging effects on cognitive function, little attention has examined the influence of TMS on AD pathogenesis. In an extensive review recently submitted for publication, we outline the limited available evidence concerning the possible mechanisms of TMS benefits, raising the possibility that protocols with documented safety in healthy young adults may have different effects in older adults, and in people at risk for AD. The view developed in this perspective piece is that defining the underlying neurobiological mechanisms responsible for the effects of TMS and other NIBS modalities will be critical in maximizing the efficacy and safety of these valuable technologies. The preclinical experimental work in this project has focused predominantly on the basic cell biological effects of TMS. These studies extend across multiple levels of analysis, including time-course studies of genome-wide gene expression in primary neuronal culture preparations, TMS effects on neuronal viability and neurite outgrowth in vitro, and microarray analysis of hippocampal and neocortical gene expression 48 hours after in vivo TMS treatment in behaviorally characterized young and aged rats. The emerging themes from this work are that TMS can exert robust, relatively enduring molecular and structural CNS effects, and importantly, that the cell biological outcome of stimulation is potently modulated by age, brain region, and cognitive status. These findings are scheduled for presentation at the 2018 annual Society for Neuroscience meeting. The important implication of the work is that accounting for the unique neurobiological condition of cognitive aging will be critical in successfully translating intervention developed in younger adults to AD and other age-related conditions.